Theory and computation of the structural and dynamic origins of protein misfolding and biomolecular electromagnetic sensing

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As life expectancy increases, we face an increasing prevalence of presently incurable diseases that severely affect the older population. One of the most common of these is cancer; another is protein misfolding disease, including Alzheimer's disease. In one component of our research program, we propose to find new therapies to diagnose or even prevent these diseases, through a fundamental understanding of the molecular mechanisms at work when these pathologies occur. Such an understanding involves quantifying energy, entropy, and structure for biomolecules. Through a suite of computational and theoretical techniques, we will elucidate the subtle molecular motions that rogue proteins undertake when they misfold. Surprisingly, a common thread may connect cancer to protein misfolding diseases. A cancer cell is a cell in a hurry, which results in a loss of protein quality control. Proteins on the surface of cancer cells may likely be misfolded. Identifying these misfolds computationally may allow us to generate drugs or antibodies that can bind selectively to proteins on cancer cells and not to healthy cells, the ultimate goal of cancer therapy. The protein whose misfolding is responsible for Lou Gehrig's disease normally functions as a molecular anti-oxidant. In an unusual plot-twist in the evolutionary story of molecular function, another protein may use its anti-oxidant behavior to actually measure the direction of the earth's magnetic field. How this protein, called cryptochrome, does this is even more bizarre, involving a quantum-mechanical mechanism where the spins of electrons precess like a top in the earth's field. Electrons are normally paired up and hidden, but a flash of blue light can separate a pair of electrons so that they become visible. Whether or not the electrons recombine or drift apart forever depends on the orientation of the protein in the earth's field, so the protein can be used as a kind of chemical compass by birds and other animals to navigate. The spin-dependent reactions that give rise to such behavior are currently a mystery; we will investigate them using new analytical approaches and tools from quantum computational chemistry, to uncover how biology may "understand" and exploit quantum mechanics.